CN1028758C - Pyrazolopyrimidinone antianginal agents - Google Patents

Pyrazolopyrimidinone antianginal agents Download PDF

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CN1028758C
CN1028758C CN91104162A CN91104162A CN1028758C CN 1028758 C CN1028758 C CN 1028758C CN 91104162 A CN91104162 A CN 91104162A CN 91104162 A CN91104162 A CN 91104162A CN 1028758 C CN1028758 C CN 1028758C
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alkyl
propyl
methyl
pyrimidin
ones
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CN1057464A (en
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安德鲁·S·贝尔
戴维·布朗
尼古拉斯·K·特列特
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Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
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Abstract

Compounds of the formula: wherein R<1> is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R<2> is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl; R<3> is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or (C3-C6 cycloalkyl)C1-C6 alkyl; R<4> taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R<6>)-piperazinyl group; R<5> is H, C1-C4 alkyl, C1-C3 alkoxy, NR<7>R<8>, or CONR<7>R<8>; R<6> is H, C1-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (R<7>R<8>N)C2-C6 alkyl, (R<7>R<8>NCO)C1-C6 alkyl, CONR<7>R<8>, CSNR<7>R<8> or C(NH)NR<7>R<8>; R<7> and R<8> are each independently H, C1-C4 alkyl, (C1-C3 alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl; and pharmaceutically acceptable salts thereof, are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.

Description

Pyrazolopyrimidinone antianginal agents
The present invention relates to a series of pyrazolos (4,3-d) pyrimidin-7-ones compounds, they be cyclic guanosine 3 ', 5 '-the potent selective depressant of single monophosphate monophosphate diesterase (cGMP PDE), can be applicable to many treatments field, comprise treatment various cardiovascular disordeies, for example stenocardia, hypertension, heart failure and atherosclerosis.
Compound of the present invention can optionally suppress cGMP PDE and do not suppress ring gland glycosides 3 ', 5 '-single monophosphate monophosphate diesterase (cAMP PDE), the result that these selectivity suppress PDE raises the cGMP level, and this can produce favourable thrombocyte anti-freezing collection activity, vasospasm activity and hemangiectasis activity, and derives from the relaxation factor (EDRF) of endothelium and the synergism of nitrated vasodilator.Therefore, these compounds can be applicable to treat multiple disease, comprise stable, unsettled and variation (Prinzmetal) stenocardia, hypertension, congestive heart failure, atherosclerosis, vessel open miopragia symptom (for example vessel open miopragia symptom behind skin transillumination coronary angioplasty), peripheral vascular disease, apoplexy, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and be the disease (for example irritable bowel trace integration disease (IBS)) of feature with the intestinal movement disorder.
It is adenosine receptor antagonists and PDE inhibitor that European patent application EP-A-0201188 discloses some pyrazolo (4,3-d) pyrimidin-7-ones compounds, can be used for treating some cardiovascular disorder such as heart failure or cardiac insufficiency.But these compounds are neither PDE inhibitor especially efficiently, and also not being specified is the selective depressant of cGMP PDE.
Compound of the present invention is formula I compound and pharmacologically acceptable salt thereof:
R wherein 1Be H, C 1-C 3Alkyl, C 3-C 5Cycloalkyl or C 1-C 3Perfluoroalkyl;
R 2For H, can be by OH, C 1-C 3Alkoxyl group or C 3-C 6The C of cycloalkyl substituted 1-C 6Alkyl or C 1-C 3Perfluoroalkyl;
R 3Be C 1-C 6Alkyl, C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 3-C 7Cycloalkyl, C 1-C 6Perfluoroalkyl or (C 3-C 6Cycloalkyl) C 1-C 6Alkyl;
R 4Constitute pyrrolidyl, piperidino-(1-position only), morpholino or 4-N-(R with the nitrogen-atoms that it connected 6)-piperazinyl;
R 5Be H, C 1-C 4Alkyl, C 1-C 3Alkoxyl group, NR 7R 8Or CONR 7R 8;
R 6Be H, C 1-C 6Alkyl, (C 1-C 3Alkoxyl group) C 2-C 6Alkyl, hydroxyl C 2-C 6Alkyl, (R 7R 8N) C 2-C 6Alkyl, (R 7R 8NCO) C 1-C 6Alkyl, CONR 7R 8, CSNR 7R 8Or C(NH) NR 7R 8;
R 7And R 8Respectively be H, C independently of one another 1-C 4Alkyl, (C 1-C 3Alkoxyl group) C 2-C 4Alkyl or hydroxyl C 2-C 4Alkyl.
In above-mentioned definition, unless otherwise noted, the alkyl or the perfluoroalkyl that contain three or more carbon atoms can be straight or brancheds.In addition, containing the alkenyl or the alkynyl of 4 or more a plurality of carbon atoms, or contain the alkoxyl group of 3 carbon atoms, can be straight or branched.
The formula I compound can contain one or more asymmetric center, therefore can exist with enantiomorph or diastereomer.The present invention had both comprised that their mixture also comprised independently single isomer.
The formula I compound can also exist with tautomeric form, and the present invention had both comprised that their mixture also comprised independently single tautomer.
The present invention also comprises the radio-labeled derivative of formula I compound, and these derivatives are suitable for carrying out biological study.
The pharmacologically acceptable salt that contains the formula I compound of basic center is the sour salify that forms with pharmaceutically acceptable acid.The example comprises hydrochloride, hydrobromate, vitriol or hydrosulfate, phosphoric acid salt or hydrophosphate, acetate, Citrate trianion, fumarate, gluconate, lactic acid salt, maleate, succinate and tartrate.The formula I compound can also form pharmaceutically useful metal-salt, particularly an alkali metal salt with alkali.The example comprises sodium salt and sylvite.
One group of preferred formula I compound is some formula I compounds like this: R wherein 1Be H, methyl or ethyl; R 2Be the C that can be replaced by OH or methoxyl group 1-C 3Alkyl; R 3Be C 2-C 3Alkyl or allyl group; R 4Constitute piperidino-(1-position only) or 4-N-(R with the nitrogen-atoms that it connected 6)-piperazinyl; R 5Be H, NR 7R 8Or CONR 7R 8; R 6Be H, C 1-C 3Alkyl, hydroxyl C 2-C 3Alkyl, CONR 7R 8, CSNR 7R 8Or C(NH) NR 7R 8; R 7And R 8Respectively be H or methyl independently of one another.
One group of particularly preferred formula I compound is some formula I compounds like this: R wherein 1Be methyl; R 2Be n-propyl; R 3Be ethyl, n-propyl or allyl group; R 4Constitute 4-N-(R with the nitrogen-atoms that it connected 6) piperazinyl; R 5Be H; R 6Be H, C 1-C 3Alkyl or 2-hydroxyethyl.
The very preferred individualized compound of the present invention comprises:
5-(2-allyloxy-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-(2-oxyethyl group-5-(piperazinyl alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-(2-oxyethyl group-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-2-oxyethyl group-5-(4-(2-propyl group) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-2-oxyethyl group-5-(4-(2-hydroxyethyl) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
1-methyl-5-(5-(piperazinyl alkylsulfonyl)-2-positive propoxy phenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-5-(4-(2-hydroxyethyl) piperazinyl alkylsulfonyl)-2-positive propoxy phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones.
The compound of logical formula I can prepare by the reaction of logical formula II compound and logical formula III compound:
R wherein 1, R 2And R 3Limit as the front, Y represents halogen atom, preferred chlorine atom.
R wherein 4And R 5Limit as the front.
This reaction is generally at room temperature carried out, and preferably carries out in the presence of as the alkanol that contains 1-3 carbon atom at a kind of solvent, and adopts excessive (III) to remove sour by product (HY).
The compound of logical formula II can be used SO 2Y group (wherein Y such as front limit) is introduced the currently known methods of aromatic nucleus, prepare by the compound of logical formula IV, for example, when Y represents the chlorine atomic time, 0 ℃ or near 0 ℃ under be prepared by the effect of chlorsulfonic acid.
R wherein 1, R 2And R 3Limit as the front.
If R 3Be to be easy to the group that removes under the chlorosulfonylation reaction conditions, as allyl group, then this group can be introduced at this synthetic final step.For example, can be as described in the embodiment 25, obtain R by the O-allyl group analogue of logical formula IV compound through the catalytic deprotection reaction of Pd 3Be the phenol of the logical formula IV of H (R wherein 1And R 2Limit as the front), make this phenol obtain logical formula II compound through chlorosulfonylation, wherein Y is Cl, R 3Be H, R 1And R 2Limit as the front.Make back one compound and suitable amine (III) reaction then, obtain the compound of logical formula I, wherein R 3Be H, R 1, R 2, R 4And R 5Limit as the front, at last its O-alkylation is obtained the compound of logical formula I, wherein R 1, R 2, R 3, R 4And R 5As formula I is limited.This alkylated reaction can carry out under standard conditions,, uses suitable haloalkane such as allyl bromide 98 that is, in the presence of alkali such as salt of wormwood, in suitable solvent such as 2-butanone, reacts under the reflux temperature of reaction mixture.In addition, this alkylated reaction also can carry out under the Mitsunobu of routine reaction conditions.
At the occasion of other formula IV compounds that should not adopt the chlorosulfonylation reaction conditions, for example R 2Be hydroxyl C 1-C 6The compound of alkyl can be protected hydroxyl with acyl group such as acetyl or benzoyl base.At this synthetic final step, under the basic hydrolysis condition of standard, remove described protecting group subsequently, obtain the compound of logical formula I, wherein R 2Be hydroxyl C 1-C 6Alkyl, R 1, R 3, R 4And R 5As formula I is limited.Some compounds of back also can be used as corresponding alkoxyl group analogue chlorosulfonylation reaction by product and obtain by way of parenthesis, that is, make R 2Be (C 1-C 3Alkoxyl group) C 1-C 6The logical formula IV compound chlorosulfonylation of alkyl then makes crude product and required amine (III) reaction, as described in embodiment 48.
The compound of logical formula IV can be used the known cyclization method that forms the pyrimidone ring, is prepared by the compound of general formula (V):
R wherein 1, R 2And R 3Limit as the front.For example, cyclization can carry out under the following conditions: being with or without hydrogen peroxide when existing, in ethanol-water media, handled (V) 2-40 hour with alkali such as sodium hydroxide or salt of wormwood down in reflux temperature.Under these conditions, also can adopt the corresponding nitrile (R wherein of logical formula VI 1, R 2And R 3Limit as the front) make the precursor of (IV).
Also can obtain the compound of logical formula IV with another kind of cyclization method, promptly the usefulness Tripyrophosphoric acid is at 140 ℃ or near 140 ℃ of following processing (V) 6-18 hour.
The compound of general formula (V) and (VI) can be respectively reacted by the compound of the compound of general formula (VII) and (VIII) and general formula (IX) and prepares:
Figure 911041621_IMG10
R wherein 1And R 2Limit as the front.
R wherein 3Limit with Y such as front.
Excessive (IX) of the general employing of this reaction, in inert solvent such as methylene dichloride, under 0 ℃-25 ℃, carried out 2-6 hour, there are excess fats family tertiary amine such as triethylamine to have the effect of removing sour by product (HY) in the reaction, also can have catalyzer such as 4-Dimethylamino pyridine to exist in the reaction to play.
The amine of formula III, formula (VII) and the amino pyrazoles of (VIII) and the carboxylic acid halides of formula (IX), if on market, can't buy, can according to the precedent of document routinely synthesis method produce by the raw material that is easy to get, and use standard reagent and reaction conditions.
Some logical formula I compound, i.e. R wherein 4Constitute 4-N-(R with the nitrogen-atoms that it connected 6)-piperazinyl, R 6Limit as the front but for hydrogen, can directly be prepared with suitable standard synthesis method by the unsubstituted corresponding piperazine analogue in 4-N position, this analogue is R 6Logical formula I compound for hydrogen.
All above-mentioned reactions all are popular response fully, the embodiment that needs only the common textbook of reference and provide later, suitable reagent and the condition that just can determine to carry out these reactions at an easy rate.Various schemes and change also are conspicuous for a person skilled in the art, thereby can prepare all compounds that formula I limits.
The following test determines of the biological activity of The compounds of this invention.
Phosphodiesterase activity
Compound is to the affinity of cGMP PDE and cAMP PDE, by measuring its IC 50Value (suppressing 50% the required inhibitor concentration of enzymic activity) is evaluated.Basically according to the method (Biochem., 10:311,1971) of W.J.Thompson etc., from tame rabbit platelet and kidney of rats, separate the PDE enzyme.CAMP PDE enzyme by tame rabbit platelet is produced the cGMP PDE enzyme of dependence calcium/calmodulin (Ca/CAM) and suppressed by cGMP separates the cGMP PDE(part I that relies on Ca/CAM simultaneously in four kinds of kidney of rats main PDE enzymes).With measuring (Biochem., 18:5228,1979) through the W.J.Thompson of modification and " in batches " method of M.M.Appleman.The result of these tests shows that The compounds of this invention all is potent selective depressant to two kinds of cGMP PDE.
Thrombocyte anti-freezing collection activity
Estimating this active method is, measure the ability of a certain compound inhibition by the external platelet aggregation effect of platelet activating factor (PAF) inductive, and the ability that strengthens the external thrombocyte anti-freezing collection effect of guanylate cyclase activator (as Nitroprusside ion and EDRF).Basic people's such as J.F.Mustard method (the Methods in Enzymol. that presses, 169:3,1989) thrombocyte crossed of preparing washing utilizes as the described standard turbidimetric technic of G.V.R.Born (J.Physiol.(Lond), 162:67P, 1962) the mensuration agglutination.
Antihypertensive active
This active evaluation is carried out after with a certain compound vein or orally give spontaneous hypertension rat.By the intubate recording blood pressure of heeling-in in clear-headed or anesthesia attitude rat carotid artery.
During to people's administration, the oral dosage of compound generally is the scope of 4-800 milligram every day concerning adult patients (70 kilograms of mean body weights) for treatment or prevention stenocardia, hypertension or congestive heart failure.For example, concerning typical adult patients, each tablet or capsule contain the 2-400 milligram active compound that fits in the suitable pharmaceutical carrier, with single dose or multiple dose administration, once a day or several times.The dosage of intravenously administrable, buccally administration or sublingual administration is general as required in the scope of each single dose 1-400 milligram.In fact, the doctor can determine to be suitable for most the concrete dosage regimen of individual patient, and this scheme will become with age, body weight and the reaction of particular patient.Above-mentioned dosage is only for the example of generalized case, but may have the individual cases that need higher or lower dosage range, and these situations within the scope of the present invention.
When being used for human body, the formula I compound can be individually dosed, but generally be and pharmaceutical carrier mixing administration, and this carrier is selected according to the route of administration and the standard pharmaceutical practice of expection.For example, these compounds can be oral, buccally administration or sublingual administration, and its form can be to contain the tablet of vehicle (as starch or lactose) or independent or with the capsule or the vaginal suppository of mixed with excipients or contain seasonings or the elixir of tinting material or suspension agent.These compounds also can parenteral injection, for example intravenous injection, intramuscularly, subcutaneous injection or intracardiac injection.During administered parenterally, preferably use with the form of aseptic aqueous solution, can contain other material in the aqueous solution, for example enough salt or glucose are so that solution and blood etc. ooze.
Therefore, another aspect of the present invention provides a kind of pharmaceutical composition, and said composition comprises a kind of formula I compound or pharmaceutically acceptable salt thereof, and said composition is used for medicine, especially for controlling human stenocardia, hypertension or congestive heart failure.
The present invention also comprises the application of formula I compound or pharmaceutically acceptable salt thereof in medication preparation, and this medicine is used for the treatment of stability, unstable and variability (Prinzmetal) stenocardia, hypertension, congestive heart failure, atherosclerosis, apoplexy, peripheral vascular disease, vessel open miopragia symptom (vessel open miopragia symptom behind skin transillumination coronary angioplasty for example, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, and be the disease (for example irritable bowel trace integration disease) of feature with the intestinal movement disorder.
The preparation method of The compounds of this invention more specifically is described with reference to EXPERIMENTAL EXAMPLE below.With Merck Kieselgel 60 F 254Chromatoplate carries out thin-layer chromatography (TLC), and the purity of compound is carried out conventional sense.With Nicolet QE-300 spectrometer record 1All the structure with hypothesis is consistent in all cases for H-NMR (Nuclear Magnetic Resonance) spectrum, these spectrum.
Embodiment 1
1-methyl-3-n-propyl pyrazoles-5-ethyl formate
(24.1g, 0.132mol) (16.8g, mixture 0.133mol) is in 90 ℃ of heating 2.5 hours down for (press Chem.Pharm.Bull., 32:1568,1984 method makes) and methyl-sulfate with 3-n-propyl pyrazoles-5-ethyl formate.This mixture is dissolved in the methylene dichloride, and washs this solution with sodium carbonate solution.Tell organic phase, dry (MgSO 4), reduction vaporization obtains solids.On silica gel (300g), carry out chromatography, use the methylene dichloride wash-out, obtain colorless oil product (20.4g, 79%).R f0.8(silica gel; Methylene chloride/acetate 80: 20: 1).
Embodiment 2
1-methyl-3-n-propyl pyrazoles-5-formic acid
With 1-methyl-3-n-propyl pyrazoles-5-ethyl formate (20.2g, 0.10mol) be suspended in the 6N aqueous sodium hydroxide solution (50ml, 0.30mol) in.This mixture was heated 2 hours down in 80 ℃, and water (50ml) dilution then is with concentrated hydrochloric acid (25ml) acidifying.Obtain light brown carboxylic acid crystal (12.3g, 71%) after the filtration, m.p.150-154 ℃.Experimental value: C, 56.99, H, 7.25; N, 16.90.C 8H 12N 2O 2Theoretical value is C, 57.13; H, 7.19; N, 16.66%.
Embodiment 3
1-methyl-4-nitro-3-n-propyl pyrazoles-5-formic acid
(12.1g 0.072mol) is added in the mixture of oleum (13ml) and nitrosonitric acid (11ml) in batches, keeps temperature to be lower than 60 ℃ simultaneously with 1-methyl-3-n-propyl pyrazoles-5-formic acid.After adding, mixture heating up is spent the night in 60 ℃, be chilled to room temperature again, be poured on ice then.Leach the nitropyrazole (11.5g, 75%) that throw out obtains white solid, m.p.124-127 ℃.Experimental value: C, 45.43; H, 5.22; N, 19.42.C 8H 11N 3O 4Theoretical value: C, 45.57; H, 5.20; N, 19.71%.
Embodiment 4
1-methyl-4-nitro-3-n-propyl pyrazoles-5-methane amide
(11.3g 0.053mol) is added in the sulfuryl chloride (50ml), and the gained mixture heating up refluxed 3 hours with 1-methyl-4-nitro-3-n-propyl pyrazoles-5-formic acid.With the reaction mixture cooling, remove excessive thionyl chloride under reduced pressure then.The oily resistates is dissolved in the acetone (50ml), and this solution is added to carefully in the mixture of ice (50g) and dense ammonium hydroxide aqueous solution (50ml).Filter collects throw out, obtains the pyrazolecarboxamide (8.77g, 78%) of light yellow solid shape, m.p.141-143 ℃.Experimental value: C, 45.22; H, 5.71; N, 26.12.C 8H 12N 4O 3Theoretical value: C, 45.28; H, 5.70; N, 26.40%.
Embodiment 5
4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide
(3.45g, 16.2mmol) (18.4g 81mmol) is suspended in the ethanol, and this mixture heating up was refluxed 2 hours with the tin chloride dihydrate with 1-methyl-4-nitro-3-n-propyl pyrazoles-5-methane amide.Gained solution is cooled to room temperature, adds the 2N aqueous sodium hydroxide solution and alkalize to pH9, and with dichloromethane extraction (3 * 150ml).Merge organic extract liquid, dry (MgSO 4), reduction vaporization.The resistates grinding that adds diethyl ether obtains the amino-pyrazol (2.77g, 94%) of pale solid shape, m.p.98-101 ℃.Experimental value: C, 52.84; H, 7.81; N, 30.38.C 8H 14N 4O theoretical value: C, 52.73; H, 7.74; N, 30.75%.
Embodiment 6
4-(2-phenetole formamido group)-1-methyl-3-n-propyl pyrazoles-5-methane amide
Under 0 ℃, at the 4-amino that is stirring-1-methyl-3-n-propyl pyrazoles-5-methane amide (3.0g, 16.4mmol), 4-Dimethylamino pyridine (0.02g, 0.164mmol) and triethylamine (3.34g, 33.0mmol) in the solution in methylene dichloride (50ml), add 2-ethoxy benzoyl chloride (6.1g, dichloromethane solution 33.0mmol) (50ml).Make the gained mixture be warmed to room temperature, restir 2 hours.Solvent evaporated under reduced pressure is dissolved in resistates in the 19:1 mixture (250ml) of methylene dichloride and methyl alcohol, then this solution is washed with 1N hydrochloric acid (100ml), dry (MgSO 4) and reduction vaporization.Crude product carries out chromatography on silica gel (200g), the 97:3 mixture wash-out with methylene dichloride and methyl alcohol obtains pink solid, with the pyrazoles-5-methane amide (2.2g, 40%) that obtains the lightpink solid state after ethyl acetate-hexane crystallization, m.p.153-155 ℃.Experimental value: C, 61.66; H, 6.77; N, 16.95.C 17H 22N 4O 3Theoretical value: C, 61.80; H, 6.71; N, 16.96%.
Embodiment 7
The 5-(2-ethoxyl phenenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
With sodium hydroxide (54g, 1.35mol) and 30% superoxol (224ml) water-soluble (2000ml) in, in this solution, add 4-(2-phenetole formamido group in batches)-1-methyl-3-n-propyl pyrazoles-5-methane amide (223g, 0.676mol).Add ethanol (700ml), the gained mixture heating up refluxed 2.5 hours, cooling, reduction vaporization then.Gained solid externally refrigerative uses 2N hydrochloric acid (380ml) to handle simultaneously, and this mixture is used dichloromethane extraction (1 * 700ml, 3 * 200ml).After merging, organic extract liquid uses saturated aqueous sodium carbonate (3 * 400ml) and salt solution (300ml) washing, drying (Na then successively 2SO 4), reduction vaporization.
Resistates carries out chromatography on silica gel (1000g), dichloromethane solution gradient (0-1%) with methyl alcohol is carried out wash-out, and then crude product is added diethyl ether (300ml) grinds, and obtains the title compound (152.2g of colorless solid shape, 72%), m.p.143-146 ℃.Experimental value: C, 65.56; H, 6.44; N, 18.14; C 17H 20N 4O 2Theoretical value: C, 65.36; H, 6.45; N, 17.94%.
Embodiment 8
5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
Under 0 ℃ and nitrogen atmosphere, with the 5-(2-ethoxyl phenenyl)-1-methyl-3-n-propyl-1, (10.0g 32.1mmol) is added in the chlorsulfonic acid (20ml) 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones in batches.After stirring is spent the night, reaction solution is added to (150ml) in the frozen water carefully, with of 9: 1 mixtures (4 * 100ml) extractions of this aqueous mixture with methylene dichloride and methyl alcohol.Extraction liquid merges after drying (Na 2SO 4), reduction vaporization obtains desired white solid SULPHURYL CHLORIDE (12.8g, 97%), m.p.179-181 ℃.Experimental value: C, 50.07; H, 4.71; N, 13.29.C 17H 19ClN 4O 4S theoretical value: C, 49.70; H, 4.66; N, 13.64%.
Embodiment 9
5-(2-oxyethyl group-5-(4-carbamyl piperidyl alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
Under room temperature; in 5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones (750mg; 1.80mmol) in the stirred suspension in ethanol (50ml); adding 4-carbamyl piperidines (703mg, 5.50mmol).The gained mixture was stirred 4 days, remove solvent then under reduced pressure.Resistates is dissolved in 9: 1 mixtures (100ml) of methylene dichloride and methyl alcohol, this solution washs with saturated aqueous sodium carbonate (100ml).Water is further used the methylene chloride-methanol mixture, and (3 * 100ml) extractions merge all organic moiety, dry (MgSO 4), reduction vaporization obtains solids.With the crystalline mixture of methyl alcohol-dimethyl formamide, obtain the title sulphonamide (446mg, 49%) of pale solid shape, m.p.274-276 ℃.Experimental value: C, 55.36; H, 6.01; N, 16.65.C 23H 29N 6O 5S theoretical value: C, 55.08; H, 5.83; N, 16.75%.
Embodiment 10-14
Method by embodiment 9 prepares following compounds with suitable amine.
Figure 911041621_IMG12
Embodiment Productive rate m.p. ultimate analysis (%)
(%) (℃) (in the bracket is theoretical value)
C H N
10
Figure 911041621_IMG14
51 161-162 54.82 6.13 17.95
（54.77 6.13 18.25）
11
Figure 911041621_IMG15
79 194-196 54.63 6.47 16.50
（54.75 6.39 16.65）
12
Figure 911041621_IMG16
88 187-189 55.61 6.23 17.74
（55.68 6.37 17.71）
13
Figure 911041621_IMG17
21 187-188 57.48 6.74 16.47
（57.35 6.82 16.72）
14 74 209-212 57.64 6.66 16.81
（57.35 6.82 16.72）
15
Figure 911041621_IMG19
18 229-230 51.25 5.56 18.92
（50.85 5.63 18.87）
Embodiment 16
5-2-oxyethyl group-5-(4-(methylthio group imido acyl group) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones hydriodate
With 5-(2-oxyethyl group-5-(4-thiocarbamyl piperazinyl alkylsulfonyl) phenyl)-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones (0.78g; 1.5mmol), methyl-iodide (426mg; 3.0mmol) and the mixture stirring and refluxing of methyl alcohol (20ml) 2 hours, make its cooling then.Leach the white solid of generation,, obtain colourless crystalline title compound (0.70g, 71%), m.p.227-228 ℃ with ethyl acetate-methanol crystallization.Experimental value: C, 41.43; H, 4.79; N, 14.42.C 23H 31N 7O 4S 2HI theoretical value: C, 41.75; H, 4.88; N, 14.82%.
Embodiment 17
5-2-oxyethyl group-5-(4-(amidino) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones hydriodate
With 5-{ 2-oxyethyl group-5-(4-(methylthio group imido acyl group) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones hydriodate (0.5g; 0.75mmol) be added in the ethanolic soln (20ml) of 33% methylamine, mixture was stirred under room temperature 18 hours.With solution decompression evaporation, the resistates grinding that adds diethyl ether.The gained solid carries out chromatography on silica gel (10g), carry out gradient elution with the dichloromethane solution of methyl alcohol, and gradient is 9-4%, the crude product grinding that adds diethyl ether, obtains light brown powder then.Obtain colourless crystalline title compound (112mg, 23%), m.p.253-255 ℃ with ethyl acetate-methanol crystallization.Experimental value: C, 42.90; H, 5.09; N, 17.41.C 23H 32N 8O 4SHI theoretical value: C, 42.86; H, 5.16, N, 17.39%.
Embodiment 18
1-methyl-4-(2-positive propoxy benzamido)-3-n-propyl pyrazoles-5-methane amide
This acid amides is pressed embodiment 6 described methods by the preparation of 2-positive propoxy Benzoyl chloride, obtains pink solid (63%), m.p.148-149 ℃.Experimental value: C, 62.97; H, 7.00; N, 16.29.C 18H 24N 4O 3Theoretical value: C, 62.77; H, 7.02; N, 16.27%.
Embodiment 19
1-methyl-5-(2-positive propoxy phenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
At 30% superoxol (1.0ml), salt of wormwood (0.54g, 3.92mmol), in the stirring the mixture of water (10ml) and ethanol (5ml), add 1-methyl-4-(2-positive propoxy benzamido)-3-n-propyl pyrazoles-5-methane amide (0.34g, 0.99mmol).This mixture heating up was refluxed 38 hours, then reduction vaporization.Resistates is suspended in the water (20ml), then with this mixture 2N hcl acidifying, and with methylene dichloride (3 * 20ml) extraction.Extraction liquid is merged dry (Na 2SO 4), reduction vaporization.The gained resistates carries out chromatography on silica gel (6g), the dichloromethane solution of using methyl alcohol obtains an oily matter with gradient (0.0-1.0%) wash-out, and the continuously grinding that adds diethyl ether obtains desired white solid product (0.19g, 59%), m.p.111-114 ℃.Experimental value: C, 66.26; H, 6.92; N, 17.15.C 18H 22N 4O 2Theoretical value: C, 66.23; H, 6.80; N, 17.17%.
Embodiment 20
5-(5-chlorosulfonyl-2-positive propoxy phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This SULPHURYL CHLORIDE is pressed the method for embodiment 8 by 5-(2-positive propoxy phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones prepares, and obtains white solid (92%).Experimental value: C, 51.26; H, 5.02; N, 12.90; C 18H 21ClN 4O 4S theoretical value: C, 50.88; H, 4.98; N, 13.19%.
Embodiment 21
1-methyl-5-(5-(piperazinyl alkylsulfonyl)-2-positive propoxy phenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This sulphonamide is pressed the method for embodiment 9 by piperazine and 5-(5-chlorosulfonyl-2-positive propoxy phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones prepares, and obtains white solid (70%), m.p.185-186 ℃.Experimental value: C, 56.17; H, 6.38; N, 17.65.C 22H 30N 6O 4S theoretical value: C, 55.67; H, 6.37; N, 17.71%.
Embodiment 22
5-5-(4-(2-hydroxyethyl) piperazinyl alkylsulfonyl)-2-positive propoxy phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This sulphonamide is pressed the method for embodiment 9 by the N-(2-hydroxyethyl) piperazine and 5-(5-chlorosulfonyl-2-positive propoxy phenyl)-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones prepares, and obtains colourless spicule (66%), m.p.158-159 ℃.Experimental value: C, 55.83; H, 6.58; N, 16.13.C 24H 34N 6O 5S theoretical value: C, 55.58; H, 6.61; N, 16.20%.
Embodiment 23
4-(2-allyloxy benzamido)-1-methyl-3-n-propyl pyrazoles-5-methane amide
At the 4-amino that is stirring-1-methyl-3-n-propyl pyrazoles-5-methane amide (3.64g, 0.02mol) pyridine moiety solution (50ml) in, drip 2-allyloxy Benzoyl chloride (3.93g, 0.02mol) dichloromethane solution (20ml), the gained mixture stirs under room temperature in dry atmosphere and spends the night.Solvent evaporated under reduced pressure, resistates are distributed between methylene dichloride (50ml) and saturated aqueous sodium carbonate (50ml).Tell organic layer, water layer carries out limit extraction with methylene dichloride again.Organic solution merges the back with 2M HCl(3 * 30ml) washing, uses salt solution (1 * 30ml) washing, dry (Na then 2SO 4).Filter and,, obtain title compound (4.525g, 66%), m.p.132-134 ℃ then crude product ethyl acetate crystallization with filtrate evaporated under reduced pressure.Experimental value: C, 63.49; H, 6.42; N, 16.33.C 18H 22N 4O 3Theoretical value: C, 63.14; H, 6.48; N, 16.36%.
Embodiment 24
5-(2-allyloxy phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
With 4-(2-allyloxy benzoylamino)-1-methyl-3-n-propyl pyrazoles-5-methane amide (1.2g, 0.0035mol), sodium hydroxide (0.70g, 0.018mol), the mixture of water (34ml) and ethanol (8ml) refluxed 5 hours.After the cooling, solution carries out limit extraction with ethyl acetate.Extraction liquid merges the back and washs with salt solution (30ml), dry (Na 2SO 4), to filter, solvent evaporated under reduced pressure obtains crude product, uses the ethyl acetate/hexane crystallization, obtains title compound (0.476g, 37%), m.p.116-119 ℃.Experimental value: C, 67.00; H, 6.21; N, 17.23.C 18H 20N 4O 2Theoretical value: C, 66.65; H, 6.21; N, 17.27%.
Embodiment 25
The 5-(2-hydroxy phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
With 5-(2-allyloxy phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones (0.25g, 0.0008mol), phenol (0.145g, 0.0015mol), piperidines (0.131g, 0.0015mol) and four (triphenyl phosphine) palladium (O) (0.046g, 0.00004mol) mixture in dehydrated alcohol (5ml) refluxes in nitrogen and spends the night.Make this mixture cooling, solvent evaporated under reduced pressure is dissolved in residue in the ethyl acetate (40ml).This solution with water (3 * 10ml), 1M HCl(3 * 10ml) and salt solution (1 * 10ml) washing.Dry (Na 2SO 4) and filter after, filtrate evaporated under reduced pressure is obtained crude product.With the ether grinding and with after ethyl acetate/pentane crystallization, obtain title phenol (0.021g, 10%), m.p.233-238 ℃.Experimental value: C, 63.17; H, 5.65; N, 19.52.C 15H 16N 4O 2Theoretical value: C, 63.36; H, 5.67; N, 19.71%.
Embodiment 26
5-(5-chlorosulfonyl-2-hydroxy phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
Under nitrogen atmosphere, with the 5-(2-hydroxy phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones (0.239g, 0.00084mol) under agitation be added in the chlorsulfonic acid (3ml) that is chilled to 0 ℃, resulting dark red solution at room temperature stirred 18 hours. in batchesThen reaction mixture is added drop-wise in the frozen water that is stirring carefully, obtains brown solid.(3 * 30ml) extractions, extraction liquid carries out drying (Na after merging with methylene dichloride with back one mixture 2SO 4) and filter, with obtaining brown solid (0.24g, 75%) after the filtrate evaporated under reduced pressure, promptly be used for next step without being further purified; R f0.3(silica gel; Methylene chloride 95: 5).
Embodiment 27
5-(2-hydroxyl-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
With 5-(5-chlorosulfonyl-2-hydroxy phenyl)-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones (0.235g, 0.0006mol) and N methyl piperazine (0.5ml, ethanolic soln 0.0045mol) (40ml) at room temperature stirred 18 hours.With this solution decompression evaporation, resistates distributes between ethyl acetate (40ml) and water (40ml).Leach thin deposit seeds, wash with water, with the ethyl acetate washing,, obtain pale powder shape title compound (0.260g, 49%), m.p.283-284 ℃ again with ethyl acetate/DMF crystallization.Experimental value: C, 53.53; H, 5.89; N, 18.40.C 20H 26N 6O 4S theoretical value: C, 53.80; H, 5.87; N, 18.82%.
Embodiment 28
5-(2-allyloxy-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
At 5-(2-hydroxyl-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-1-methyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones (0.103g; 0.00023mol) and salt of wormwood (0.032g; 0.00023mol) in the stirred suspension in 2-butanone (10ml); (0.02ml 0.00023mol), refluxes this mixture heating up 8 hours to add allyl bromide 98.After the cooling, with this reaction mixture reduction vaporization, resistates is suspended in the water (20ml).(3 * 20ml) extractions, extraction liquid carries out drying (Na after merging to this aqueous suspensions with ethyl acetate 2SO 4), filter the back reduction vaporization and obtain oily matter.On silica gel (2g), carry out column chromatography, dichloromethane solution gradient (0-3%) wash-out with methyl alcohol, get suitable fraction then and carry out reduction vaporization, obtain the semi-solid thing, it is dissolved in acetone, this solution decompression evaporation is obtained title compound (0.011g, 10%), m.p.151-153 ℃, R f0.5(silica gel; Methylene chloride 95: 5), m/e 487(M ++ 1).
Embodiment 29
4-(2-phenetole formyl ammonia)-1,3-dimethyl pyrazole-5-methane amide
This acid amides is pressed the method for embodiment 6 by 4-amino-1, and 3-dimethyl pyrazole-5-methane amide (pressing J.Med.Chem.30:91,1987 method preparation) prepares, and obtains white solid (81%), m.p.178-181 ℃.Experimental value: C, 59.89; H, 6.05; N, 18.44.C 15H 18N 4O 3Theoretical value: C, 59.59; H, 6.00; N, 18.53%.
Embodiment 30
The 5-(2-ethoxyl phenenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazoles (4,3-d) pyrimidin-7-ones
With 4-(2-phenetole formamido group)-1, (1.6g 5.29mmol) is added in the Tripyrophosphoric acid (50g) 3-dimethyl pyrazole-5-methane amide, and this mixture was heated 6 hours in 140 ℃.With this solution cooling, pour in the frozen water (100ml), then this mixture is alkalized with 10% aqueous sodium hydroxide solution, with methylene dichloride (3 * 100ml) extractions.Merge organic extract liquid, dry (MgSO 4), reduction vaporization.Resistates carries out chromatography on silica gel, with 97: 3 mixture wash-outs of methylene dichloride and methyl alcohol.Crude product aqueous ethanol crystallization obtains the title compound of colorless solid shape, m.p.201-204 ℃.Experimental value: C, 63.43; H, 5.57; N, 19.35.C 15H 16N 4O 2Theoretical value: C, 63.36; H, 5.67; N, 19.71%.
Embodiment 31
5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This SULPHURYL CHLORIDE is pressed the method for embodiment 8 by the 5-(2-ethoxyl phenenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones prepares, and obtains white solid with quantitative yield.R f0.3(silica gel; Ether).Use without being further purified promptly.
Embodiment 32-34
The method of pressing embodiment 9 is by 5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-1,3-dimethyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones and suitable amine prepare following compounds.
Figure 911041621_IMG20
Embodiment m.p. ultimate analysis (%)
Figure 911041621_IMG21
Productive rate (℃) (in the bracket is theoretical value)
（%） C H N
32
Figure 911041621_IMG22
68 225-226 53.88 5.81 18.42
（53.79 5.87 18.82）
33
Figure 911041621_IMG23
68 240-242 53.07 5.77 19.27
（52.76 5.59 19.43）
34
Figure 911041621_IMG24
62 228-229 53.23 5.87 17.72
（52.93 5.92 17.63）
Embodiment 35
4-nitro-3-n-propyl pyrazoles-5-formic acid
Method by embodiment 3 makes 3-n-propyl pyrazoles-5-formic acid (pressing Chem.Pharm.Bull.32:1568,1984 method preparation) nitrated, obtains the title compound (75%) of colorless solid shape, m.p.169-173 ℃.Experimental value: C, 42.35; H, 4.56; N, 21.07.C 7H 9N 3O 4Theoretical value: C, 42.21; H, 4.55; N, 21.10%.
Embodiment 36
4-nitro-3-n-propyl pyrazoles-5-methane amide
With 4-nitro-3-n-propyl pyrazoles-5-formic acid (7.8g, 39.2mmol) and the mixture heating up of sulfuryl chloride (35ml) refluxed 3 hours.Remove solvent under reduced pressure, solid residue is added under 0 ℃ in the ammonium hydroxide aqueous solution (40ml) in batches.Then with this mixture water (60ml) dilution, with 9: 1 mixtures (3 * 100ml) extractions of methylene dichloride and methyl alcohol.Merge organic moiety, dry (MgSO 4) and reduction vaporization, the resistates alcohol crystal obtains the methane amide (1.0g, 13%) of colorless solid shape, m.p.202-206 ℃.Experimental value: C, 42.35; H, 5.01; N, 28.38.C 7H 10N 4O 3Theoretical value: C, 42.42; H, 5.09; N, 28.27%.
Embodiment 37
4-amino-3-n-propyl pyrazoles-5-methane amide
With 4-nitro-3-n-propyl pyrazoles-5-methane amide (198mg, methanol solution 1.0mmol) (5ml) be added drop-wise to sodium borohydride (113mg, 2.97mmol), in the mixture of 10% palladium/carbon (5mg) and water (3ml).This mixture was stirred under room temperature 3 hours, filter, remove solvent under reduced pressure.Resistates obtains the title compound (61mg, 36%) of pale solid shape, m.p.196-201 ℃ with ethyl acetate-recrystallizing methanol.R f0.4(silica gel; Methylene chloride/ammonium hydroxide 90: 10: 1).Experimental value: C, 48.96; H, 6.98; N, 32.08.C 7H 12N 4O theoretical value: C, 49.98; H, 7.19; N, 33.31%.
Embodiment 38
4-(2-phenetole formamido group)-3-n-propyl pyrazoles-5-methane amide
This title amide is prepared by 4-amino-3-n-propyl pyrazoles-5-methane amide by the method for embodiment 6, obtains white solid (64%), m.p.209-211 ℃.Experimental value: C, 60.73; H, 6.41; N, 17.80.C 16H 20N 4O 3Theoretical value: C, 60.74; H, 6.37; N, 17.71%.
Embodiment 39
The 5-(2-ethoxyl phenenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title compound by the method for embodiment 30 by 4-(2-phenetole formamido group)-3-n-propyl pyrazoles-5-methane amide prepares, and obtains white solid (16%), m.p.199-201 ℃.Experimental value: C, 64.44; H, 6.19; N, 18.44%.C 16H 18N 4O 2Theoretical value: C, 64.41; H, 6.08; N, 18.78%.
Embodiment 40
5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title SULPHURYL CHLORIDE is pressed the method for embodiment 8 by the 5-(2-ethoxyl phenenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones prepares, and obtains white solid (78%).R f0.25(silica gel; Ether).
This compound uses without being further purified promptly.
Embodiment 41
5-(2-oxyethyl group-5-(4-methylpiperazine base) alkylsulfonyl phenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title sulphonamide is pressed the method for embodiment 9 by 5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones prepares, and obtains white solid (70%), m.p.236-239 ℃.Experimental value: C, 54.84; H, 6.27; N, 18.10.C 21H 28N 6O 4S theoretical value: C, 54.76; H, 6.13; N, 18.25%.
Embodiment 42
3-brooethyl-5-chloro-1-methyl-4-nitropyrazole
With N-bromo-succinimide (10.7g 60.0mmol) is added to 5-chloro-1,3-dimethyl-4-nitropyrazole (8.78g, in carbon tetrachloride solution 50.0mmol) (100ml), in visible light (150W tungsten lamp) irradiation with vlil 3 days.In entire reaction course, add a certain amount of benzoyl peroxide (6 * 50mg) at certain intervals.Remove solvent under reduced pressure, resistates carries out chromatography on silica gel, with 1: 1 mixture wash-out of methylene dichloride and hexane, obtains the bromide (8.0g, 63%) of pale solid shape, m.p.80-82 ℃.Experimental value: C, 23.95; H, 2.05; N, 16.31.C 5H 5BrClN 3O 2Theoretical value: C, 23.60; H, 1.98; N, 16.51%.
Embodiment 43
5-chloro-3-methoxymethyl-1-methyl-4-nitropyrazole
(5.0g, (5.75g 33.8mmol) handles methanol solution 19.6mmol) (50ml), and this mixture heating up was refluxed 2 hours with Silver Nitrate with 3-brooethyl-5-chloro-1-methyl-4-nitropyrazole.With reaction mixture cooled and filtered, filtrate evaporated under reduced pressure.Resistates is distributed between ethyl acetate (100ml) and water (50ml), and water is used a certain amount of ethyl acetate (50ml) extraction again.Merge organic extract liquid, dry (MgSO 4) and reduction vaporization.On silica gel, carry out chromatography,, obtain the title pyrazoles (1.6g, 40%) of white solid, m.p.59-63 ℃ with 97: 3 mixture wash-outs of methylene dichloride and methyl alcohol.Experimental value: C, 34.65; H, 3.83; N, 20.05.C 6H 8ClN 3O 3Theoretical value: C, 35.05; H, 3.92; N, 20.44%.
Embodiment 44
5-cyano group-3-methoxymethyl-1-methyl-4-nitropyrazole
With 5-chloro-3-methoxymethyl-1-methyl-4-nitropyrazole (205mg, 1.0mmol), potassium cyanide (130mg, spend the night by acetonitrile solution (2ml) reflux 2.0mmol) and hexaoxacyclooctadecane-6-6-(10mg).Solvent evaporated under reduced pressure, resistates are distributed between ethyl acetate (20ml) and water (20ml).Tell organic phase, dry (MgSO 4), reduction vaporization, resistates carries out chromatography on silica gel then, with 1: 1 mixture wash-out of ethyl acetate and pentane.The crude product grinding that adds diethyl ether obtains yellow solid (30mg, 19%), m.p.48-50 ℃.Experimental value: C, 42.89; H, 4.15; N, 28.78.C 7H 8N 4O 3Theoretical value: C, 42.86; H, 4.11; N, 28.56%.
Embodiment 45
4-amino-5-cyano-3-methoxymethyl-1-methylpyrazole
This title compound is prepared by 5-cyano group-3-methoxymethyl-1-methyl-4-nitropyrazole by the method for embodiment 5, obtains pale solid (68%), m.p.82-84 ℃.Experimental value: C, 50.81; H, 6.13; N, 33.94.C 7H 10N 4O theoretical value: C, 50.59; H, 6.07; N, 33.72%.
Embodiment 46
5-cyano group-4-(2-phenetole formamido group)-3-methoxymethyl-1-methylpyrazole
This title compound is prepared by 4-amino-5-cyano-3-methoxymethyl-1-methylpyrazole by the method for embodiment 6, obtains pale solid (61%), m.p.103-105 ℃.Experimental value: C, 61.21; H, 5.98; N, 17.80.C 16H 18N 4O 3Theoretical value: C, 61.13; H, 5.77; N, 17.83%.
Embodiment 47
The 5-(2-ethoxyl phenenyl)-and 3-methoxymethyl-1-methyl isophthalic acid, 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title compound is pressed the method for embodiment 7, by 5-cyano group-4-(2-phenetole formamido group)-3-methoxymethyl-1-methylpyrazole prepares by the pilot process that generates 5-primary amide derivative on the spot, obtain white solid (38%), m.p.160-161 ℃.Experimental value: C, 61.35; H, 5.75; N, 17.98.C 16H 18N 4O 3Theoretical value: C, 61.13; H, 5.77; N, 17.83%.
Embodiment 48
3-methoxymethyl-1-methyl-5-(5-(4-methylpiperazine base alkylsulfonyl)-2-ethoxyl phenenyl)-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
Under 0 ℃, with the 5-(2-ethoxyl phenenyl)-3-methoxymethyl-1-methyl isophthalic acid, (470mg 1.50mmol) is dissolved in the chlorsulfonic acid (3ml) 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones.This solution was stirred under room temperature 2 hours, be added to carefully then in the frozen water (50ml).Gained solution neutralizes with saturated sodium carbonate solution, uses 20: 1 mixture extractions (2 * 50ml) of methylene dichloride and methyl alcohol then.Organic extract liquid merges the back reduction vaporization, and resistates is dissolved in the ethanol (5ml), and (450mg 4.5mmol) handles with N methyl piperazine with this solution.After at room temperature handling 1 hour, solvent evaporated under reduced pressure, resistates carries out chromatography on silica gel, with mixture (volume ratio is 90: 10: the 1) wash-out of methylene dichloride, methyl alcohol and ammonium hydroxide aqueous solution.Crude product adds ethyl acetate and grinds, and obtains the title compound (49mg, 7%) of white solid, m.p.198-199 ℃.Experimental value: C, 52.94; H, 6.04; N, 17.67.C 21H 28N 6O 5S theoretical value: C, 52.93; H, 5.92; N, 17.64%.
Also from ethyl acetate and methanol mixture, isolated 3-hydroxymethyl-1-methyl-5-(5-(4-methylpiperazine base the alkylsulfonyl)-2-ethoxyl phenenyl of white solid after chromatography and the crystallization)-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones (51mg; 7%), m.p.209-210 ℃.Experimental value: C, 51.94; H, 5.77; N, 18.05.C 20H 26N 6O 5S theoretical value: C, 51.94; H, 5.67; N, 18.17%.
Embodiment 49
1-ethyl-3-n-propyl pyrazoles-5-ethyl formate
This pyrazoles is prepared by 3-n-propyl pyrazoles-5-ethyl formate and ethyl sulfate by embodiment 1 described method, obtains colorless oil (72%).R f0.5(silica gel; Ethyl acetate/hexane 1: 1).
Embodiment 50
1-ethyl-3-n-propyl pyrazoles-5-formic acid
This carboxylic acid is prepared by 1-ethyl-3-n-propyl pyrazoles-5-ethyl formate by embodiment 2 described methods, obtains light brown solid (89%), m.p.73-77 ℃.Experimental value: C, 58.62; H, 7.69; N, 15.23.C 9H 14N 2O 2Theoretical value: C, 59.32; H, 7.74; N, 15.37%.
Embodiment 51
1-ethyl-4-nitro-3-n-propyl pyrazoles-5-formic acid
This title compound is prepared by 1-ethyl-3-n-propyl pyrazoles-5-formic acid by embodiment 3 described methods, obtains colorless solid (96%), m.p.120-123 ℃.Experimental value: C, 47.61; H, 5.81; N, 18.54.C 9H 13N 3O 4Theoretical value: C, 47.57; H, 5.77; N, 18.49%.
Embodiment 52
1-ethyl-4-nitro-3-n-propyl pyrazoles-5-methane amide
This title amide is prepared by 1-ethyl-4-nitro-3-n-propyl pyrazoles-5-formic acid by embodiment 4 described methods, obtains pale solid (86%), m.p.119-120 ℃.Experimental value: C, 47.38; H, 6.18; N, 24.34.C 9H 14N 4O 3Theoretical value: C, 47.78; H, 6.24; N, 24.77%.
Embodiment 53
4-amino-1-ethyl-3-n-propyl pyrazoles-5-methane amide
This title compound is prepared by 1-ethyl-4-nitro-3-n-propyl pyrazoles-5-methane amide by embodiment 5 described methods, obtains pale solid (100%), m.p.93-97 ℃.Experimental value: C, 55.17; H, 8.34; N, 28.93.C 9H 16N 4O theoretical value: C, 55.08; H, 8.22; N, 28.55%.
Embodiment 54
4-(2-phenetole formamido group)-1-ethyl-3-n-propyl pyrazoles-5-methane amide
This title compound is prepared by 4-amino-1-ethyl-3-n-propyl pyrazoles-5-methane amide and 2-ethoxy benzoyl chloride by embodiment 6 described methods, obtains colorless solid (73%), m.p.139-141 ℃.Experimental value: C, 63.03; H, 7.15; N, 16.50.C 18H 24N 4O 3Theoretical value: C, 62.77; H, 7.02; N, 16.27%.
Embodiment 55
The 5-(2-ethoxyl phenenyl)-and 1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title compound by the method for embodiment 7 by 4-(2-phenetole formamido group)-1-ethyl-3-n-propyl pyrazoles-5-methane amide prepares, and obtains colorless solid (46%), m.p.112-114 ℃.Experimental value: C, 66.59; H, 6.85; N, 17.26.C 18H 22N 4O 2Theoretical value: C, 66.23; H, 6.79; N, 17.17%.
Embodiment 56
5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-and 1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title compound is pressed the method for embodiment 8 by the 5-(2-ethoxyl phenenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones prepares, and obtains its dichloromethane solvent thing (86%), m.p.170-172 ℃.Experimental value: C, 49.82; H, 4.84; N, 12.77.C 18H 21ClN 4O 4S1/6CH 2Cl 2Theoretical value: C, 49.70; H, 4.90; N, 12.77%.
Embodiment 57
5-(2-oxyethyl group-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title compound is pressed the method for embodiment 9 by 5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-1-ethyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones and N methyl piperazine prepare, and obtain colorless solid (43%), m.p.160-162 ℃.Experimental value: C, 57.24; H, 6.17; N, 16.83.C 23H 32N 6O 4S theoretical value: C, 56.54; H, 6.60; N, 17.20%.R f0.35(silica gel; Methylene chloride 9: 1).
Embodiment 58
5-2-oxyethyl group-5-(4-(2-hydroxyethyl) piperazine alkylsulfonyl) phenyl }-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones
This title sulphonamide is pressed the method for embodiment 9 by 5-(5-chlorosulfonyl-2-ethoxyl phenenyl)-1-ethyl-3-n-propyl-1; 6-dihydro-7H-pyrazolo (4; 3-d) pyrimidin-7-ones and N-(2-hydroxyethyl) piperazine prepares, and obtains colorless solid (88%), m.p.191-193 ℃.Experimental value: C, 55.74; H, 6.55; N, 15.78.C 24H 34N 6O 5S theoretical value: C, 55.58; H, 6.61; N, 16.20%.

Claims (6)

1, a kind of method for preparing following formula: compound and pharmacologically acceptable salt thereof,
Figure 911041621_IMG2
R wherein 1Be H or C 1-C 3Alkyl;
R 2Be H or can be by OH or C 1-C 3The C that alkoxyl group replaces 1-C 6Alkyl;
R 3Be C 1-C 6Alkyl or C 3-C 6Alkenyl;
R 4Constitute piperidino-(1-position only) or 4-N-(R with the nitrogen-atoms that it connected 6)-piperazinyl;
R 5Be H, NR 7R 8Or CONR 7R 8
R 6Be H, C 1-C 6Alkyl, hydroxyl C 2-C 6Alkyl, CSNR 7R 8Or C (NH) NR 7R 8
R 7And R 8Respectively be H or C independently of one another 1-C 4Alkyl;
This method comprises: make following formula: compound
R wherein 1, R 2And R 3Limit as the front, Y is chlorine, bromine or fluorine, reacts with following formula: compound
Figure 911041621_IMG4
R wherein 4And R 5Limit as the front;
And when needed desired product is converted into pharmacologically acceptable salt.
2, the method for claim 1, wherein R 1, R 2, R 4And R 5According to claim 1, R 3Be H, after this method, then carry out the O-alkylation of phenol, and when needed desired product is converted into pharmacologically acceptable salt.
3, method as claimed in claim 1 or 2, wherein R 1, R 4And R 5According to claim 1, R 3As claimed in claim 1 or 2, R 2Contain a hydroxyl substituent that is subjected to the protection of acetyl or benzoyl base, described protecting group removes with alkali hydrolysis method in subsequent reactions, and then as required desired product is converted into pharmacologically acceptable salt.
4, as each described method, wherein R among the claim 1-3 1Be H, methyl or ethyl; R 2Be the C that can be replaced by OH or methoxyl group 1-C 3Alkyl; R 3Be C 2-C 3Alkyl or allyl group; R 4Constitute piperidino-(1-position only) or 4-N-(R with the nitrogen-atoms that it connected 6)-piperazinyl; R 5Be H, NR 7R 8Or CONR 7R 8; R 6Be H, C 1-C 3Alkyl, hydroxyl C 2-C 3Alkyl, CSNR 7R 8Or C(NH) NR 7R 8; R 7And R 8Respectively be H or methyl independently of one another.
5, method as claimed in claim 4, wherein R 1Be methyl; R 2Be n-propyl; R 3Be ethyl, n-propyl or allyl group; R 4Constitute 4-N-(R with the nitrogen-atoms that it connected 6)-piperazinyl; R 5Be H; R 6Be H, C 1-C 3Alkyl or 2-hydroxyethyl.
6, method as claimed in claim 5, wherein prepared described formula I compound is selected from following compound and pharmacologically acceptable salt thereof:
5-(2-allyloxy-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-(2-oxyethyl group-5-(piperazinyl alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-(2-oxyethyl group-5-(4-methylpiperazine base alkylsulfonyl) phenyl)-and 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-2-oxyethyl group-5-(4-(2-propyl group) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-2-oxyethyl group-5-(4-(2-hydroxyethyl) piperazinyl alkylsulfonyl) phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
1-methyl-5-(5-(piperazinyl alkylsulfonyl)-2-positive propoxy phenyl)-and 3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones;
5-5-(4-(2-hydroxyethyl) piperazinyl alkylsulfonyl)-2-positive propoxy phenyl }-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones.
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